This invention relates to novel pyridylfuran and pyridylthiophene compounds, their pharmaceutically effective salts, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and/or cell adhesion molecule mediated diseases, and pharmaceutical compositions for use in such therapy.
Cytokines possess a multitude of regulatory and inflammatory effects. Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis (RA), osteoarthritis (OA), endotoxemia and/or toxic shock syndrome, other acute and chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease (IBD), tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including RA, rheumatoid spondylitis, OA, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS), cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection such as influenza, cachexia secondary to infection or malignancy, cachexia, cancer, secondary to acquired immune deficiency syndrome (AIDS), ARC (AIDS related complex), keloid formation, diabetes, obesity, scar tissue formation. Crohn""s disease, ulcerative colitis or pyresis. The concept of anti-TNF therapy has been validated by the demonstration that soluble TNF receptor and neutralizing monoclonal antibodies (MAbs) against TNF showed therapeutic efficacy in a variety of preclinical and clinical studies (e.g., Elliott, M. J. et al., The Lancet, 1994, 344, 1125. Dullemen, H. M. V. et al., Gastroenterology, 1995. 109, 129.)
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including neutrophils, mononuclear cells, fibroblasts, endothelial cells, epithelial cells and keratinocytes. Elevated IL-8 levels have been reported in joint fluids in RA, gouty arthritis, psoriatic scale and ARDS. Its production from endothelial cells is induced by IL-1, TNF or lipopolysachharide (LPS). IL-8 has been shown to have chemoattractant properties for neutrophils, T-lymphocytes and basophils. In addition, it promotes angiogenesis as well as neutrophil activation, including lysozomal enzyme release and respiratory burst. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils, which may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased IL-8 production would benefit by compounds which suppress of IL-8 production.
Cellular movement and adhesion are a fundamental biological response to external stimuli. During an inflammatory response, leukocytes must leave the plasma compartment and migrate to the point of antigenic insult. The mechanism of this migratory event is a complex interplay between soluble mediators and membrane-bound cellular adhesion molecules. Soluble cellular chemotactic factors, which are produced in the damaged tissue by a variety of resident cells, set up a chemical concentration gradient out to the plasma compartment. Interaction of these factors with their receptors on leukocytes leads to a directional migration of the leukocytes toward increasing concentrations of the chemotactic factor. Simultaneously, various adhesion molecules are upregulated on the leukocyte which mediate the initial rolling on the endothelial tissue, binding to a specific ligand on the activated endothelial tissue, and finally migration between endothelial cells into the tissue. The steps in this cascade of events are mediated by the interaction of specific cell surface proteins, termed xe2x80x9ccell adhesion molecules (CAM)xe2x80x9d. E-selectin (ELAM-1, endothelial leukocyte adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1), and VCAM-1 (vascular cell adhesion molecule-1) are three major adhesion molecules the expression of which on endothelial cells is upregulated upon treatment with inflammatory stimuli. ICAM-1 is expressed at low levels on resting endothelium and is markedly induced in response to cytokines such as IL-1, TNF and interferon-xcex3 (IFN-xcex3). VCAM-1 is not expressed in resting endothelium but is induced by IL-1, TNF and IL-4. Induction of both ICAM-1 and VCAM-1 occurs 4 to 6 hours after cytokine treatment and cell surface expression remains elevated for up to 72 hours after treatment with cytokines. On the other hand, induction of transcription of the E-selectin gene by cytokines such as IL-1 and TNF results in an increase in the expression on the surface of endothelial cells peaking approximately 4-6 hours after challenge, and returns toward a basal level of expression by 24 hours.
The concept of anti-CAM therapy has been validated by the demonstration that MAbs against ICAM-1 and antisense oligonucleotide against ICAM-1 showed therapeutic efficacy in a variety of preclinical and clinical studies (A. F. Kavanaugh et al., Arthritis Rheum, 1994, 37, 992; C. E. Haug et al., Transplantation, 1993, 55, 766; and J. E. Jr. Sligh et al., Proc. Natl. Acad. Sci., 1993, 90, 8529). Further support comes from the reports of the in vivo activity of sLeX and related carbohydrates, which are antagonists of E-selectin mediated adhesion ( M. S. Mulligan et al., Nature, 1993, 364, 149-151). Thus, the potential therapeutic targets for CAM inhibitors range from, but are not limited to, RA, IBD and psoriasis to ischemia/reperfusion injury, autoimmune diabetes, organ transplantation, ARDS, tumor metastases and AIDS, as is evident from the many ongoing development activities. The regulation of the functions of CAM is of benefit in controlling, reducing and alleviating many of these disease states. There remains a need for compounds which are capable of inhibiting cytokine production and/or CAM expression. The pyridylfuran and pyridylthiophene compounds of the present invention are shown herein in an in vitro assay to inhibit cytokine production and/or CAM expression.
Japanese Kokai (laid-open) Publication Number H02-289548 discloses aryl substituted pyridine compounds as anti-ischemia agents. Japanese Kokai (laid-open) Publication Number H03-232884 discloses a variety of thiophene compounds as a herbicide.
The present invention provides a compound of the formula: 
and its pharmaceutically effective salts, wherein
R1 and R2 are independently selected from the following:
(a) hydrogen, halo, R5xe2x80x94, R6xe2x80x94, C2-6 alkenyl, C2-6 alkynyl, hydroxy-R5xe2x80x94, R5xe2x80x94Oxe2x80x94, R5xe2x80x94Sxe2x80x94, hydroxy-R6xe2x80x94, R5xe2x80x94Oxe2x80x94R5xe2x80x94, mercapto-R5xe2x80x94, R5xe2x80x94Sxe2x80x94R5xe2x80x94, xe2x80x94NH2, R5xe2x80x94NHxe2x80x94, R6xe2x80x94NHxe2x80x94, (R5)2xe2x80x94Nxe2x80x94 or heterocyclic group optionally substituted by one or two substituents selected from C1-4 alkyl, phenyl and pyridyl;
(b) Arxe2x80x94, Arxe2x80x94R5xe2x80x94, Arxe2x80x94C2-6 alkenyl, Arxe2x80x94C2-6 alkynyl, Arxe2x80x94Oxe2x80x94, Arxe2x80x94Oxe2x80x94Arxe2x80x94, Arxe2x80x94Oxe2x80x94Arxe2x80x94Oxe2x80x94, Arxe2x80x94Oxe2x80x94R5xe2x80x94, Arxe2x80x94R5xe2x80x94Oxe2x80x94, Arxe2x80x94Sxe2x80x94, Arxe2x80x94R5xe2x80x94Sxe2x80x94, Arxe2x80x94NHxe2x80x94, (Ar)2xe2x80x94R5xe2x80x94, Arxe2x80x94R5xe2x80x94NHxe2x80x94, Arxe2x80x94R5xe2x80x94N(R5)xe2x80x94 or (Ar)2xe2x80x94Nxe2x80x94;
(c) R5xe2x80x94C(O)xe2x80x94, xe2x80x94NO2, cyano, NH2xe2x80x94C(O)xe2x80x94, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, (R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94, Arxe2x80x94C(O)xe2x80x94, (Arxe2x80x94R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94, Arxe2x80x94NHxe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, R5xe2x80x94S(O)2xe2x80x94 or R5xe2x80x94S(O)xe2x80x94; and
(d) R5xe2x80x94C(O)xe2x80x94NHxe2x80x94, Arxe2x80x94C(O)xe2x80x94NHxe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94NHxe2x80x94 or H2Nxe2x80x94C(O)xe2x80x94NHxe2x80x94;
wherein Ar is aryl or heteroaryl optionally substituted with one or two substituents selected from C1-4 alkyl, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, hydroxy, amino and halo; and
wherein R5 is C1-6 alkyl optionally substituted by up to four (preferably up to three) halogen atoms and R6 is C3-8 cycloalkyl optionally substituted by up to four (preferably up to three) halogen atoms;
R3 is selected from the following:
(e) R6, R5, cyano, formyl, R5xe2x80x94C(O)xe2x80x94, R6xe2x80x94C(O)xe2x80x94, C2-6 alkenyl-C(O)xe2x80x94, C2-6 alkynyl-C(O)xe2x80x94, R5xe2x80x94C(O)xe2x80x94R5xe2x80x94, R6xe2x80x94C(O)xe2x80x94R5xe2x80x94, R5xe2x80x94C(O)xe2x80x94R6xe2x80x94, R6xe2x80x94C(O)xe2x80x94R6xe2x80x94, C2-6 alkenyl-C(O)xe2x80x94R5xe2x80x94, C2-6 alkynyl-C(O)xe2x80x94R5xe2x80x94, R5xe2x80x94C(O)xe2x80x94C2-6 alkenylene-, R5xe2x80x94C(O)xe2x80x94C2-6 alkynylene-, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94R5xe2x80x94, R6xe2x80x94Oxe2x80x94C(O)xe2x80x94R5xe2x80x94, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94C2-6 alkynylene-, R5xe2x80x94Sxe2x80x94C(O)xe2x80x94, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94R5xe2x80x94, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, R6xe2x80x94NHxe2x80x94C(O)xe2x80x94, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, R6xe2x80x94NHxe2x80x94C(O)xe2x80x94R5xe2x80x94, (R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94, (R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94R5xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, R6xe2x80x94NHxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, (R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, R5xe2x80x94Oxe2x80x94R5xe2x80x94Oxe2x80x94, R5xe2x80x94Oxe2x80x94R5xe2x80x94, HOxe2x80x94R5xe2x80x94, R5xe2x80x94Oxe2x80x94R6xe2x80x94, HOxe2x80x94R6xe2x80x94 or Ar;
(f) R5xe2x80x94C(O)xe2x80x94NHxe2x80x94, Arxe2x80x94C(O)xe2x80x94NHxe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NH2, R5xe2x80x94NHxe2x80x94, (R5)2xe2x80x94Nxe2x80x94, xe2x80x94R6xe2x80x94NH2, xe2x80x94R5xe2x80x94NH2, R5xe2x80x94NHxe2x80x94R5xe2x80x94, R6xe2x80x94NHxe2x80x94R5xe2x80x94, R5xe2x80x94NHxe2x80x94R6xe2x80x94, (R5)2xe2x80x94Nxe2x80x94R5xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94NHxe2x80x94, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94, (R5)2xe2x80x94Nxe2x80x94C(O)xe2x80x94NHxe2x80x94, Arxe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94, (Ar)2xe2x80x94Nxe2x80x94C(O)xe2x80x94NHxe2x80x94, HOxe2x80x94Nxe2x95x90C(R5)xe2x80x94, HOxe2x80x94Nxe2x95x90Cxe2x80x94, HOxe2x80x94Nxe2x95x90CHxe2x80x94R5xe2x80x94, HOxe2x80x94Nxe2x95x90CHxe2x80x94R6xe2x80x94, R5xe2x80x94C(O)xe2x80x94Oxe2x80x94Nxe2x95x90CHxe2x80x94, R5Oxe2x80x94Nxe2x95x90CHxe2x80x94, R6Oxe2x80x94Nxe2x95x90CHxe2x80x94, R5Oxe2x80x94Nxe2x95x90C(R5)xe2x80x94, R6Oxe2x80x94Nxe2x95x90C(R5)xe2x80x94, R5Oxe2x80x94Nxe2x95x90C(R6)xe2x80x94, R5Oxe2x80x94Nxe2x95x90CHxe2x80x94R5xe2x80x94, R6Oxe2x80x94Nxe2x95x90CHxe2x80x94R5xe2x80x94, R5Oxe2x80x94Nxe2x95x90CHxe2x80x94R6xe2x80x94, R6Oxe2x80x94Nxe2x95x90CHxe2x80x94R6xe2x80x94, HOxe2x80x94NHxe2x80x94, R5Oxe2x80x94NHxe2x80x94, HOxe2x80x94N(R5)xe2x80x94, R5Oxe2x80x94N(R5)xe2x80x94, HOxe2x80x94NHxe2x80x94R5xe2x80x94, R5Oxe2x80x94NHxe2x80x94R5xe2x80x94, HOxe2x80x94N(R5)xe2x80x94R5xe2x80x94 or R5Oxe2x80x94N(R5)xe2x80x94R5xe2x80x94;
(g) R5xe2x80x94Sxe2x80x94, Arxe2x80x94Sxe2x80x94, R5xe2x80x94S(O)xe2x80x94, R5xe2x80x94NHxe2x80x94S(O)2xe2x80x94, R5xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2NH2, xe2x80x94S(O)NH2, R5xe2x80x94NHxe2x80x94S(O)xe2x80x94, Arxe2x80x94S(O)xe2x80x94, Arxe2x80x94R5xe2x80x94S(O)xe2x80x94, Arxe2x80x94S(O)2xe2x80x94, C2-6 alkenyl-S(O)2xe2x80x94, C2-6 alkynyl-S(O)2xe2x80x94, Arxe2x80x94R5xe2x80x94S(O)2xe2x80x94, Arxe2x80x94NHxe2x80x94S(O)2xe2x80x94, Arxe2x80x94R5xe2x80x94NHxe2x80x94S(O)2xe2x80x94, Arxe2x80x94NHxe2x80x94S(O)xe2x80x94 or Arxe2x80x94R5xe2x80x94NHxe2x80x94S(O)xe2x80x94; and
(h) Arxe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94, Arxe2x80x94C(O)xe2x80x94R5xe2x80x94, Arxe2x80x94C(O)xe2x80x94R6xe2x80x94, Arxe2x80x94C(O)xe2x80x94C2-6 alkenylene-, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94R5xe2x80x94, Arxe2x80x94R5xe2x80x94C(O)xe2x80x94C2-6 alkenylene-, Arxe2x80x94C2-6 alkenylene-C(O)xe2x80x94, Arxe2x80x94C2-6 alkynylene-C(O)xe2x80x94, Arxe2x80x94C2-6 alkenylene-C(O)xe2x80x94R5xe2x80x94, Arxe2x80x94C2-6 alkynylene-C(O)xe2x80x94R5xe2x80x94, Arxe2x80x94Oxe2x80x94R5xe2x80x94C(O)xe2x80x94, Arxe2x80x94Sxe2x80x94R5xe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94Sxe2x80x94C(O)xe2x80x94, Arxe2x80x94NHxe2x80x94C(O)xe2x80x94, Arxe2x80x94R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, (Ar)2xe2x80x94C2-6 alkenylene-C(O)xe2x80x94, (Ar)2xe2x80x94C2-6 alkynylene-C(O)xe2x80x94, (Ar)2xe2x80x94R5xe2x80x94Sxe2x80x94C(O)xe2x80x94, (Ar)2xe2x80x94Nxe2x80x94C(O)xe2x80x94 or (Ar)2xe2x80x94R5xe2x80x94NHxe2x80x94C(O)xe2x80x94;
wherein Ar, R5 and R6 are as defined above; or
two of R1, R2 and R3 together form a group of the formula xe2x80x94A1xe2x80x94B1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94B1xe2x80x94A3xe2x80x94B2xe2x80x94A2xe2x80x94 which, together with the carbon atoms to which A1 and A2 are attached, defines a ring having 4 to 8 ring atoms, the ring optionally being substituted with acetyl, xe2x80x94C(O)xe2x80x94OH, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94OR5, xe2x80x94C(O)xe2x80x94NHR5, hydroxy, R5xe2x80x94, C1-4 alkoxy, R5xe2x80x94NHxe2x80x94, R6xe2x80x94NHxe2x80x94, (R5)2Nxe2x80x94, piperidino, piperazino, pyrrolidino or Ar, wherein A1 and A2 are independently a direct bond or C1-6 alkylene and A3 is C1-4 alkylene and B1 and B2 are independently a direct bond, O, S, S(O), S(O)2, C(O) or NR5;
R4 is selected from the following:
(i) hydrogen, halo, R5xe2x80x94, hydroxy-R5xe2x80x94 or R5xe2x80x94Oxe2x80x94R5xe2x80x94; and
(j) R5xe2x80x94C(O)xe2x80x94, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94 or R5xe2x80x94NHxe2x80x94C(O)xe2x80x94; or
two of R4 which are attached to adjacent carbon atoms on the pyridine ring complete a fused benzene ring, the benzene ring being optionally substituted with one or two substituents selected from C1-4 alkyl, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, nitro, hydroxy, amino and halo;
wherein R5 is as defined above;
X is O, S, S(O) or S(O)2;
m is 0, 1, 2, 3 or 4; and
the nitrogen atom of the pyridyl ring attached to the 5-position of the furan or the thiophene ring is optionally replaced by a N oxide group.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from AIDS, ARC, arthritis, asthma, bone resorption disease, cachexia, cardiovascular disease including atherosclerosis, cerebral malaria, Crohn""s disease, diabetes, fever or myalgia due to infection, gout, graft versus host reaction, inflammation of organs, inflammatory bowel disease, keloid formation, psoriasis, pulmonary inflammatory disease, respiratory distress syndrome, reperfusion injury, rhinitis, scar tissue formation, sepsis, septic shock, silicosis, toxic shock syndrome, transplant rejection, ulcerative colitis, and other disorders and conditions that are cytokine- or CAM-mediated, in a mammal, comprising an amount of the compound of formula (I), or a pharmaceutically effective salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a disorder or condition selected from AIDS, ARC, arthritis, asthma, bone resorption disease, cachexia, cardiovascular disease including atherosclerosis, cerebral malaria, Crohn""s disease, diabetes, fever or myalgia due to infection, gout, graft versus host reaction, inflammation of organs, inflammatory bowel disease, keloid formation, psoriasis, pulmonary inflammatory disease, respiratory distress syndrome, reperfusion injury, rhinitis, scar tissue formation, sepsis, septic shock, silicosis, toxic shock syndrome, transplant rejection, ulcerative colitis, and other disorders or conditions that are cytokine- or CAM-mediated, in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of formula (I), or a pharmaceutically effective salt thereof, that is effective in treating such a disorder or condition.
The invention also relates to a pharmaceutical composition for treating a disorder or condition, the treatment of which can be effected or facilitated by reducing or inhibiting a cytokine mediator or CAM mediator of said disorder or condition in a mammal, comprising an amount of a compound of formula (I), or a pharmaceutically effective salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
The invention also relates to a method for treating a disorder or condition, the treatment of which can be effected or facilitated by reducing or inhibiting a cytokine mediator or CAM mediator of said disorder or condition in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of formula (I), or a pharmaceutically effective salt thereof, that is effective in treating such disorder or condition.
The term xe2x80x9ctreatingxe2x80x9d as used herein refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d as used herein refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals of 1 to 12 carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkyl radicals having one to about 6 atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary-butyl, and the like.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d means carbocyclic saturated radicals, of 3 to 8 carbon atoms, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
As used herein, the term xe2x80x9calkenylxe2x80x9d means straight or branched chain unsaturated radicals of 2 to 12 carbon atoms. More preferred alkenyl radicals are xe2x80x9clower alkenyl radicals having one to about 6 atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. The double bonds of these substituents are preferably separated from the remaining part of the compound I by at least one saturated carbon atom. There may be mentioned also by way of example vinyl, prop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl and but-3-en-1-yl.
As used herein, the term xe2x80x9chalosubstituted alkylxe2x80x9d refers to an alkyl radical as described above substituted with one or more halogens included, but not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.
As used herein, the term xe2x80x9calkenylenexe2x80x9d means a straight or branched hydrocarbon chain spacer radical having one double bond including, for example, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHCH(CH3)xe2x80x94, and the like.
As used herein, the term xe2x80x9calkynylxe2x80x9d is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butyyl and the like.
As used herein, the term xe2x80x9calkynylenexe2x80x9d means a straight or branched hydrocarbon chain spacer radical having one triple bond including, for example, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1CCH2xe2x80x94, xe2x80x94Cxe2x89xa1CCH(CH3)xe2x80x94, and the like.
As used herein, the term xe2x80x9carylxe2x80x9d means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl, and the like.
As used herein, the term xe2x80x9cheterocyclicxe2x80x9d means saturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperidinyl, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholino, morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl, etc.].
As used herein, the term xe2x80x9cheteroarylxe2x80x9d means unsaturated heterocyclic radicals. Examples of heteroaryl radicals include unsaturated 5 to 6 membered heterocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [1H-tetrazolyl, 2H-tetrazolyl, etc.], unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl, etc.], unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, etc.]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., benzoxazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, etc.]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, etc.], and the like. The term also means radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
As used herein, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo and iodo.
As used herein, the term xe2x80x9cN oxide groupxe2x80x9d means a group represented by the following formula: 
As used herein, the term xe2x80x9cequivalent of R2axe2x80x94C(O)xe2x80x94CH2xe2x80x94R7xe2x80x9d means compounds with similar reactivity to R2axe2x80x94C(O)xe2x80x94CH2xe2x80x94R7, or compounds which can be transformed to R2axe2x80x94C(O)xe2x80x94CH2xe2x80x94R7 in situ, such as enamine equivalent R2axe2x80x94C(NH2)xe2x95x90CHxe2x80x94R7, or enolether equivalent R2axe2x80x94C(OR3a)xe2x95x90CHxe2x80x94R7.
In the formula (I), a substituent of substituted R6 (for example, hydroxy-R6xe2x80x94, carboxy-R6xe2x80x94, R6xe2x80x94Oxe2x80x94R6xe2x80x94, etc.) may be attached to any carbon atom of the R6.
In the group xe2x80x9c(Ar)2xe2x80x94R6xe2x80x94xe2x80x9d, two of Ar may be the same or different from each other, and may be attached to a same carbon atom or different carbon atoms of R6.
A preferred group of compounds of this invention includes the compound of the formula (I) wherein the heterocyclic group is selected from piperidino, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl and morpholino; and the aryl or heteroaryl group is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, pyrrolyl, indolyl, benzothienyl and benzofuryl.
Also, a preferred group of compounds of this invention includes the compound of the formula (I) wherein R1 is selected from group (a), (b) and (c); R2 is selected from group (a), (b) and (c); R3 is selected from group (e), (f), (g) and (h); and R4 is selected from group (i); or two of R1, R2 and R3 together form a group of the formula xe2x80x94A1xe2x80x94B1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94B1xe2x80x94A3xe2x80x94B2xe2x80x94A2xe2x80x94; X is O or S; and m is 0, 1 or 2.
A further preferred compound of the invention includes the compound of formula (I) wherein R1 is Arxe2x80x94Oxe2x80x94, Arxe2x80x94Oxe2x80x94Arxe2x80x94Oxe2x80x94, Arxe2x80x94R5xe2x80x94N(R5)xe2x80x94, R5xe2x80x94S(O)2xe2x80x94, R5xe2x80x94S(O)xe2x80x94, hydrogen, R5xe2x80x94Sxe2x80x94, R5xe2x80x94Oxe2x80x94, a heterocyclic group selected from piperidino, piperidinyl, piperazinyl and morpholino, the heterocyclic group being optionally substituted by one or two of C1-4 alkyl, phenyl or pyridyl, halo, R5xe2x80x94, R5xe2x80x94C(O)xe2x80x94 or Ar optionally substituted with C1-4 alkyl, hydroxy, nitro, C1-4 alkylthio, halo-substituted C1-4 alkyl, C1-4 alkoxy or halo; R2 is hydrogen, halo, R5-, Arxe2x80x94 or R5xe2x80x94C(O)xe2x80x94, wherein the aryl or heteroaryl ring of Ar is optionally substituted with C1-4 alkyl, hydroxy, nitro or halo; R3 is R5xe2x80x94, R5xe2x80x94C(O)xe2x80x94, Ar, R5xe2x80x94NHxe2x80x94C(O)xe2x80x94, R5xe2x80x94C(O)xe2x80x94NHxe2x80x94, cyano, formyl, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94R5xe2x80x94, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94R5xe2x80x94, HOxe2x80x94Nxe2x95x90CHxe2x80x94, R5Oxe2x80x94Nxe2x95x90CHxe2x80x94, R5xe2x80x94C(O)xe2x80x94Oxe2x80x94Nxe2x95x90CHxe2x80x94, HOxe2x80x94NHxe2x80x94R5xe2x80x94, Arxe2x80x94C(O)xe2x80x94 or Arxe2x80x94S(O)2xe2x80x94; R2 and R3 are at the 4 and 3-positions of the furan or the thiophene ring, respectively; or two of R1, R2 and R3 together form a group of the formula xe2x80x94A1xe2x80x94B1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94B1xe2x80x94A3xe2x80x94B2xe2x80x94A2xe2x80x94 which, together with the carbon atoms to which A1 and A2 are attached, defines a ring having 5 to 7 ring atoms, the ring optionally being substituted with acetyl, hydroxy, R5xe2x80x94, C1-4 alkoxy, wherein A1 and A2 are independently a direct bond or C1-6 alkylene and A3 is C1-4 alkylene and B1 and B2 are independently a direct bond, O, S, S(O) or C(O); and m is 0.
A further preferred compound of the invention includes the compound of formula (I) wherein R1 is hydrogen, fluoro, chloro, C1-4 alkyl, C1-4 alkylthio, C1-4 alkyl-C(O)xe2x80x94, phenoxy optionally substituted with one or two fluorine atoms, piperidino, piperazinyl optionally substituted by C1-4 alkyl, morpholino, halophenoxyphenoxy, phenyl-C1-4 alkyl-N(C1-4 alkyl)-, C1-4 alkyl-S(O)2xe2x80x94, phenyl, pyridyl or thienyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with C1-4 alkyl, C1-4 alkylthio, C1-4 alkoxy, hydroxy, trifluoromethyl, fluoro or chloro; R2 is hydrogen, chloro, fluoro, C1-4 alkyl, phenyl, pyridyl or C1-4 alkyl-C(O)xe2x80x94; R3 is C1-4 alkyl, fluoro-C1-4 alkyl, difluoro-C1-4 alkyl, cyano, C1-4 alkyl-Oxe2x80x94C(O)xe2x80x94C1-4 alkyl, C1-4 alkyl-Oxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94, H2Nxe2x80x94C(O)xe2x80x94C1-4 alkyl, C1-4 alkyl-NHxe2x80x94C(O)xe2x80x94, C1-4 alkyl-C(O)xe2x80x94Oxe2x80x94Nxe2x95x90CHxe2x80x94, C1-4 alkyl-Oxe2x80x94Nxe2x95x90CHxe2x80x94, HOxe2x80x94NHxe2x80x94C1-4 alkyl, HOxe2x80x94Nxe2x95x90Cxe2x80x94, pyrrolyl-S(O)2xe2x80x94, phenyl-C(O)xe2x80x94, formyl, C1-4 alkyl-C(O)xe2x80x94, phenyl, pyridyl, C1-4 alkyl-NHxe2x80x94C(O)xe2x80x94 or C1-4 alkyl-C(O)xe2x80x94NHxe2x80x94; xe2x80x94A1xe2x80x94Bxe2x80x94A2xe2x80x94 is C1-6 alkylene-C(O)xe2x80x94C1-6 alkylene, C1-6 alkylene-C(O)xe2x80x94 or xe2x80x94Sxe2x80x94CH(acetyl)-C1-4 alkylene; and xe2x80x94A1xe2x80x94B1xe2x80x94A3xe2x80x94B2xe2x80x94A2xe2x80x94 is C1-6 alkylene-Sxe2x80x94C(O)xe2x80x94.
A particularly preferred compound of the invention includes the compound of formula (I) wherein R1 is chloro, methyl, ethyl, phenyl, 4-pyridyl, isopropyl, isobutyl, acetyl, hydrogen, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluorophenyl, 4-fluorophenyl, thienyl, 4-methylthiophenyl, morpholino, 4-methylpiperazinyl, N-benzyl-N-methylamino, phenoxy, 3-(4-fluorophenoxy)-phenoxy, methyl-S(O)2xe2x80x94, methylthio, piperidino, 2-fluorophenyl, 2-fluorophenoxy, 2,5-difluorophenoxy or 4-fluorophenoxy; R2 is hydrogen, methyl, ethyl, acetyl, pyridyl or phenyl; R3 is methyl, ethyl, pyridyl, acetyl, propanoyl, acetamnino, methylaminocarbonyl, 1-hydroxyethyl, methoxycarbonyl, pyrrolinine-1-sulfonyl, cyano, phenyl-C(O)xe2x80x94, formyl, HOxe2x80x94Nxe2x95x90Cxe2x80x94, CH3xe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94, (CH3)2Nxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94, ethoxy-C(O)xe2x80x94(CH2)2xe2x80x94, methylamino-C(O)xe2x80x94, CH3xe2x80x94C(O)xe2x80x94Oxe2x80x94Nxe2x95x90CHxe2x80x94, H2Nxe2x80x94C(O)xe2x80x94, isopropoxy-C(O)xe2x80x94, CH3Oxe2x80x94Nxe2x95x90CHxe2x80x94, difluoromethyl, fluoromethyl, HOxe2x80x94NHxe2x80x94CH2xe2x80x94 or H2Nxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94; xe2x80x94A1xe2x80x94Bxe2x80x94A2xe2x80x94 is selected form xe2x80x94(CH2)3xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)2xe2x80x94C(CH3)2xe2x80x94C(O)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)4xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94CH(acetyl)-CH(CH3)xe2x80x94 and xe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94; and xe2x80x94A1xe2x80x94B1xe2x80x94A3xe2x80x94B2xe2x80x94A2xe2x80x94 is xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94C(O)xe2x80x94.
A particularly preferred compound of the invention also includes the compound of formula (I) wherein R1 is chloro, methyl, ethyl, phenyl, 4-pyridyl, isopropyl, isobutyl or acetyl; R2 is hydrogen, methyl, ethyl or acetyl; R3 is methyl, ethyl, pyridyl, acetyl or propanoyl; and xe2x80x94A1xe2x80x94Bxe2x80x94A2xe2x80x94 is xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94 or xe2x80x94(CH2)3xe2x80x94C(O)xe2x80x94.
Among the compounds of the formula (I), particularly preferred individual compounds are one of the following:
3-acetyl-2,4-dimethyl-5-(4-pyridyl)furan;
3-methyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetahydrobenzofuran;
3-acetyl-4-methyl-2-phenyl-5-(4-pyridyl)furan;
3-acetoamino-2,4-dimethyl-5-(4-pyridyl)furan;
2,4-dimethyl-3-methylaminocarbonyl-5-(4-pyridyl)furan;
4-oxo-2-(4-pyridyl)-3,5,5-trimethyl4,5,6,7-tetrahydrobenzofuran;
4-oxo-2-(4-pyridyl)-3,7,7-trimethyl4,5,6,7-tetrahydrobenzofuran;
3-methyl-4-oxo-2-(4-pyridyl)cyclohepteno(b)furan;
3-acetyl-2-isobutyl-4-methyl-5-(4-pyridyl)furan hydrochloride;
6,7-dihydro-3,6-dimethyl-2-(4-pyridyl)-furo[3,2-c]pyran-4-one;
3-ethyl-7,7-dimethyl-4-oxo-2-(4pyridyl)-4,5,6,7-tetrahydrobenzofuran;
7,7-dimethyl-3-phenyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydrobenzofuran;
2-acetyl-4-methyl-3,5-di(4-pyridyl)thiophene;
2-acetyl-3-methyl-4,5-di(4-pyridyl)thiophene;
3-acetyl-4-methyl-2,5-di(4-pyridyl)thiophene;
4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-benzo(b)thiophene;
3-acetyl-5-chloro-4-methyl-2-(4-pyridyl)thiophene;
3-acetyl-2,4-dimethyl-5-(4-pyridyl)thiophene;
3-acetyl-4-methyl-2-phenyl-5-(4-pyridyl)thiophene;
3-methyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydrobenzothiophene;
2,5-di(4-pyridyl)-3-(1-hydroxyethyl)4-methylthiophene;
1,3-di(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophen-4-one;
2,5-di(4-pyridyl)-3-methoxycarbonylthiophene;
3-acetyl-2,5-di(4-pyridyl)thiophene;
2,5-di(4-pyridyl)-3-(pyrrolidine-1-sulfonyl))thiophene;
2,5-di(4-pyridyl)-3-ethyl-4-methylthiophene dihydrochloride;
4-acetyl-3-methyl-2-(4-pyridyl)thiophene;
3-acetyl-2-(4-methoxyphenyl)-4-methyl-5-(4-pyridyl)thiophene hydrochloride;
3-cyano-2,5-di(4-pyridyl)thiophene;
3-acetyl-2-(4-chlorophenyl)-4-methyl-5-(4-pyridyl)thiophene hydrochloride;
3-acetyl-4-methyl-2-(4-trifluoromethylphenyl)-5-(4-pyridyl)thiophene hydrochloride;
3-acetyl-2-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)thiophene;
3-benzoyl-2,5-di(4-pyridyl)thiophene;
2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde;
3-acetyl-4-methyl-5-(4-pyridyl)-2-(3-thienyl)thiophene;
3-acetyl-4-methyl-5-(4-pyridyl)-2-(4-methylthiophenyl)thiophene;
3-acetyl-2-(4-morpholino)-5-(4-pyridyl)thiophene;
3-acetyl-2-(4-methylpiperazin-1-yl)-5-(4-pyridyl)thiophene;
2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime dihydrochloride;
3-acetyl-2-(N-benzyl-N-methylamino)-5-(4-pyridyl)thiophene hydrochloride;
1,3-di(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
3-acetyl-2-phenoxy-5-(4-pyridyl)thiophene;
2-acetyl-3,4-dimethyl-5-(4-pyridyl)thieno[2,3-b]thiophene;
3-acetyl-2-{3-(4-fluorophenoxy)phenoxy}-5-(4-pyridyl)thiophene hydrochloride;
1-chloro-3-(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
3-methanesulfonyl-1-(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
3-methylthio-1-(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
[2,5-di-(4-pyridyl)3-thienyl]butan-3-one;
N,N-dimethyl-3-[2,5-di-(4-pyridyl)3-thienyl]propionamide;
3-acetyl-2-(1-piperidino)-5-(4-pyridyl)thiophene;
ethyl 3-[2,5-di-(4-pyridyl)3-thienyl]propionate dihydrochloride;
N-methyl-{2,5-di(4-pyridyl)thiophen-3-yl}carboxamide;
3-(2-fluorophenyl)-1-(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
1-chloro-3-(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
O-acetyl-2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime;
3-acetyl-2-(2-fluorophenoxy)-5-(4-pyridyl)thiophene;
3-acetyl-2-(2,5-difluorophenoxy)-5-(4-pyridyl)thiophene;
3-(4-fluorophenyl)-1-(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
2,5-di(4-pyridyl)-3-thiophenecarboxamide;
3-(isopropyloxycarbonyl)-2,5-di(4-pyridyl)thiophene;
O-methyl-2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime dihydrochloride;
3-acetyl-2-(4-fluorophenoxy)-5-(4-pyridyl)thiophene;
1-(4-pyridyl)-3-(3-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
3-difluoromethyl-2,5-di(4-pyridyl)-4-methylthiophene;
2,5-di(4-pyridyl)-3-fluoromethyl-4-methylthiophene;
1-(4-pyridyl)-3-(4-trifluoromethylphenyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
1-(4-fluorophenyl)-3-(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
3-(N-benzyl-N-methylamino)-1-(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one;
[2,5-di(4-pyridyl)-4-methylthiophen-3-yl]methylhydroxylamine trihydrochloride; and
3-[2,5-di-(4-pyridyl)3-thienyl]propionamide.
Among the compounds of the formula (I), the most preferred individual compounds are one of the following:
3-acetyl-2,4-dimethyl-5-(4-pyridyl)furan;
3-methyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydrobenzofuran;
4-oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydrobenzofuran;
3-ethyl-7,7-dimethyl-4-oxo-2-(4-pyridyl)4,5,6,7-tetrahydrobenzofuran;
3-acetyl-4-methyl-2,5-di(4-pyridyl)thiophene;
1,3-di(4-pyridyl)-5,6-dihydro-4H-cyclopenta(c)thiophen-4-one;
2,5-di(4-pyridyl)-3-methoxycarbonylthiophene;
3-acetyl-2,5-di(4-pyridyl)thiophene;
2,5-di(4-pyridyl)-3-ethyl-4-methylthiophene dihydrochloride;
3-acetyl-2-(4-chlorophenyl)-4-methyl-5-(4-pyridyl)thiophene hydrochloride;
3-acetyl-4-methyl-2-(4-trifluoromethylphenyl)-5-(4-pyridyl)thiophene hydrochloride;
3-acetyl-2-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)thiophene;
3-benzoyl-2,5-di(4-pyridyl)thiophene;
2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde;
2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime dihydrochloride;
1,3-di(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
3-methylthio-1-(4-pyridyl)-4,5,6,7-tetrahydrobenzo(c)thiophen-4-one;
[2,5-di-(4-pyridyl)3-thienyl]butan-3-one;
N,N-dimethyl-3-[2,5-di-(4-pyridyl)3-thienyl]propionamide;
O-acetyl-2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime;
3-(isopropyloxycarbonyl)-2,5-di(4-pyridyl)thiophene;
O-methyl-2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde oxime dihydrochloride;
3-difluoromethyl-2,5-di(4-pyridyl)4-methylthiophene;
2,5-di(4-pyridyl)-3-fluoromethyl-4-methylthiophene;
[2,5-di(4-pyridyl)-4-methylthiophen-3-yl]methylhydroxylamine trihydrochloride; and 3-[2,5-di-(4-pyridyl)3-thienyl]propionamide.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are outlined as follows.
The compounds of formula (I) can be prepared by using the method of Stille or Suzuki (for example, Snieckus V. et al., J. Org. Chem., 1995, 60, 292, Stille, J. K. Angew. Chem. Int. Ed. Engl., 1986, 25, 508, Mitchell, M. B. et al., Tetrahedron Lett., 1991, 32, 2273, Matteson, D. S., Tetrahedron, 1989, 45, 1859). 
(wherein R is an organometallic group such as trialkylstannyl, dialkylboronyl, boric acid or zinc halide such as zinc chloride, zinc bromide or zinc iodide; R1, R2, R3, R4 and X are as already defined above; and Y is halo such as Cl, Br or I)
As shows in Scheme 1, the pyridylfuran and pyridylthiophene compounds (I) can be prepared by a reaction of compound (1-1) with furyl or thienyl halides (1-2), in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium(II) chloride, in the inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, preferably dioxane under suitable conditions. The thiophene oxide (I, Xxe2x95x90S(O)) or thiophene dioxide (I, Xxe2x95x90S(O)2) compounds can be also prepared by a reaction of compound (1-1) with thiophene oxide halide (1-2, Xxe2x95x90S(O)) or thiophene dioxide halide (1-2, Xxe2x95x90S(O)2) in a similar reaction condition.
The reaction of trialkyl(4-pyridyl)stannane (1-1) with furyl or thienyl halides (1-2) may be carried out in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, preferably dioxane, typically in the presence of lithium chloride and a catalyst. The catalyst may be selected from those typically employed for the so-called Stille reaction (for example, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium(II) chloride). The reaction may be run at a temperature in a range from 20 to 160xc2x0 C., preferably 60 to 130xc2x0 C., for 10 minutes to 5 days, usually 30 minutes to 15 hours.
The reaction of dialkyl(4-pyridyl)borane (1-1) swith furyl or thienyl halides (1-2) may be carried out in an inert solvent such as benzene, toluene, tetrahydrofuran, preferably toluene, typically in the presence of a base such as potassium hydroxide, triethylamine, sodium ethoxide, sodium acetate or quaternary ammonium halide, preferably potassium hydroxide. The catalyst may be selected from those typically employed for the so-called Suzuki reaction (for example, tetrakis(triphenyiphosphine)palladium or bis(triphenvlphosphine)palladium(II) chloride). The reaction is run at a temperature in the range from 20 to 160xc2x0 C., preferably 60 to 130xc2x0 C. for 10 minutes to 5 days, usually 30 minutes to 15 hours.
The reaction of 4-pyridineboronic acid (1-1) with furyl or thienyl halides (1-2) may be carried out in a solvent such as benzene, toluene, dimethoxyethane, dimethylformamide, preferably dimethoxyethane, typically in the presence of a base such as potassium hydroxide, triethylamine, sodium bicarbonate, preferably sodium bicarbonate, or a combination of water and above compounds, preferably water and dimethoxyethane. The catalyst may be selected from those typically employed for the so-called Suzuki reaction (for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) chloride, or {bis(diphenylphosphino)butane}palladium(II) chloride). The reaction is run at a temperature in the range from 20 to 160xc2x0 C., usually 60 to 130xc2x0 C. for 10 minutes to 5 days, usually 30 minutes to 15 hours.
The procedures and conditions to carry out these coupling reactions are known to those in the art, and described in several technical literatures. For example, the procedures of Gronowitz, S. et al. and Snieckus, V. et al. for alkylstannanes are described in J. Het. Chem., 1990, 27, 2165, and J. Org. Chem., 1995, 60, 292; the procedure of Terashima, M. et al. for alkyl boranes is in Heterocycles, 1984, 22, 265 and 2471, and in Chem. Pharm. Bull., 1983, 31, 4573; and the procedures of Fischer, F. C., Mitchel, M. B. et al. and McKillop, A. et al. for boric acids are in a J. Red. Trav. Chim. Pays-Bays, 1965, 84, 439, Tetrahedron Lett., 1991, 32, 2273, and Tetrahedron, 1992, 48, 8117.
The 4-organometallopyridines (1-1) (Rxe2x95x90Sn, B or Zn) can be prepared according to the procedure of the above literatures. The requisite furyl or thienyl halides (1-2) are either commercially available or can be prepared from the corresponding furans and thiophenes by halogenation known in the art. The furans and thiophenes for halogenation are either commercially available or can be prepared by using methods known in the art, for example, Paal-Knorr""s method, Feist-Benary""s method, Knorr""s method and Hinsberg""s method (Tetrahedron, 1995, 51, 13271).
The compounds of formula (1-2) (R1=alkylamino, arylamino, or cyclic amino) can be prepared by a reaction of compound (1-3) with an appropriate alkylamine, arylamine or cyclic amine such as piperidine, piperazine, or morpholine, without solvent as shown in Scheme 2. This reaction proceeds at a temperature in the range from 20 to 250xc2x0 C. preferably 80 to 150xc2x0 C. for 10 minutes to 3 days. usually 30 minutes to 15 hours. This reaction may also be carried out in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium or bis(tri-o-tolylphosphine)palladium(II) chloride, in the inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, preferably dioxane under suitable conditions. The procedures and conditions to carry out these coupling reactions are known to those in the art, (for example, Buchwald, S. L. et al., Angew. Chem. Int. Ed. Engl., 1995, 34, 1348.) This reaction can be applied to (1-4) for the synthesis of (I) as shown in Scheme 3. 
As shown in Scheme 4, the compounds of formula (1-2) (R1=alkoxy, aryloxy, alkylthio, arylthio) can be prepared by a reaction of compound (1-3) with an appropriate alcohol or thiol such as alkylalcohol, alkylthiol, phenol or thiophenol and an appropriate base such as sodium hydride, potassium hydride, sodium hydroxide, preferably sodium hydride in the presence of a catalyst such as copper metal, copper(I) iodide, and copper(I) bromide, preferably copper(I) iodide in the inert solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, benzene, toluene, xylene, tetrahydrofuran, dioxane, preferably dimethylformamide. This reaction proceeds at a temperature in the range from 20 to 250xc2x0 C., preferably 80 to 150xc2x0 C. for 10 minutes to 3 days, usually 30 minutes to 15 hours. This reaction can be applied to (1-4) for the synthesis of (I) as shown in Scheme 5. 
As apparent to one skilled in the art, the compound (I) can be also obtained from a reaction of the compound (1-1) wherein R is halo and the compound (1-2) wherein Y is replaced by an organometallic group such as Me3Snxe2x80x94, Bu3Snxe2x80x94, Et2Bxe2x80x94, (HO)2Bxe2x80x94 or zinc halide. The replacement of a halogen atom by the organometallic group can be carried out by the halogen-metal exchange, followed by a reaction of appropriate reagents such as trimethyltin chloride, tributyltin chloride, diethyl methoxyborane or trimethyl borate.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of formula (I) can be prepared by using the method of Paal-Knoll or Knorr as shown in Scheme 6. 
Pyridylfurans (2-2) can be prepared by the intramolecular cyclization of 1,4-dione (2-1) with acid catalyst such as H2SO4, P2O5, ZnCl2, Ac2O, TiCl4, PPA, and the like, preferably PPA. Pyridylthiophenes (2-3) can be prepared by the reaction of 1,4-dione (2-1) with P2S3, P2S5, H2S, and the like.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
As the pyridylfuran and pyridylthiophene compounds of this invention may possess at least one asymmetric center, they are capable of occurring in various stereoisomeric forms or configurations. Hence, the compounds can exist in separated (+)- and (xe2x88x92)-optically active forms, as well as in racemic or (xc2x1)-mixtures thereof. The present invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
Insofar as the pyridylfuran and pyridylthiophene compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned pyridylfuran and pyridylthiophene base compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate))salts among others.
The pharmaceutically acceptable salts of the present invention also include alkali or alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Quaternary salts obtained from compounds of the invention and C1-4 alkyl halide are also included. The other pharmaceutically acceptable salts which can be used in the present invention are described in J. Pharmaceutical Sciences, 1977, 66, 1-19. These salts can be prepared by conventional procedures.
The compounds (I) of this invention prepared as mentioned above inhibit inflammatory stimuli-induced cytokine production such as tumor necrosis factor alpha (TNF-xcex1) and interleukin-1xcex2 (IL-1xcex2), and are useful in the treatment or alleviation of various cytokine-mediated diseases such as asthma, arthritis, inflammatory bowel disease (IBD), sepsis, septic shock, rhinitis, inflammation of organs (e.g. hepatitis), AIDS and various inflammatory diseases. Furthermore, the compounds of this invention inhibit inflammatory stimuli-induced synthesis of proteins that regulate adhesion of leukocytes to other leukocytes and to other cell types and have potential use in the treatment of inflammatory and immune disorders such as arthritis and IBD; cardiovascular diseases, psoriasis and transplant rejection.
The pyridylfuran and pyridylthiophene compounds of formula (I) of this invention, or their pharmaceutically effective salts, can be administered via either the oral, parenteral (e.g., intravenous, intramuscula or subcutaneous) or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 10 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. For example, a dosage level that is in the range of from 0.06 mg to 2 mg per kg of body weight per day is most desirably employed for the treatment of inflammation. The compound of the invention can be administered either in a single daily dose or divided doses (e.g., 2-4 times/day).
The compounds (I) of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The ability of the compounds of the formula (I) to inhibit TNFxcex1 biosynthesis and CAMs expression may be demonstrated in vitro by the following procedures.
L929 cells are grown in minimum essential medium (MEM) (Gibco BRL NY) supplemented with 10% FCS, 50 U/mL penicillin and 50 xcexcg/mL streptomycin. Human umbilical vein endothelial cells (HUVECs) are obtained from Morinaga and grown in endothelial growth medium (E-GM UV, Kurabou, Japan) supplemented with 10% fetal calf serum (FCS, Biowhitakker, Walkersville, Md.), 10 ng/mL EGF, 1 xcexcg/mL hydrocortisone, and 1:100 dilution of bovine brain extract (Kurabou, Japan ) in 5% CO2 at 37xc2x0 C. Cells of a human promyelocytic cell line, HL-60, are grown in RPMI-1640 (Nissui Seiyaku, Tokyo, Japan) supplemented with 10% FCS plus penicillin (50 U/mL) and streptomycin (50 xcexcg/mL).
The ability of the compounds of the formula (I) to inhibit TNFxcex1 biosynthesis may be demonstrated in vitro by the following procedure 2.
Human peripheral blood mononuclear cells (HPBMNC) are isolated from heparinized human whole blood by Ficoll-Paque (Pharmacia, Sweden) density centrifugation, washed with Ca-Mg free phosphate-buffered saline (PBS, Nissui Seiyaku, Tokyo, Japan), suspended in RPMI 1640 containing 10% FCS and plated into 48 well plates (Falcon, Becton Dickinson, New Jersey) at 2xc3x97106 cells/well. Monocytes (HMo) are allowed to adhere to the plate by incubating at 37xc2x0 C. for 1 hour, then the supernatant is aspirated and refilled with fresh RPMI-1640 medium containing 1% FCS.
Test compounds are prepared as 100 mM dimethyl sulfoxide (DMSO) stock solutions and diluted with media to obtain final testing concentrations. HMo are incubated at 37xc2x0 C. for 4 hours in the presence of LPS (E. coli. 055:B5, Difco, MI) (10 xcexcg/mL) with the test compounds in dose ranges of about 0.1 xcexcMxcx9c100 xcexcM. The assay is run in a volume of 200 xcexcL/well. Supernatants are subjected to quantitation of TNFxcex1 by an L929 cell cytotoxicity assay or by TNF enzyme immuno assay.
L929 cell cytotoxicity assay: On the day of the experiment, L929 cells are detached by trypsin treatment, washed with MEM and resuspended with 1% FCS-containing MEM. L929 cells (8xc3x97105 cells/well) in a volume of 50 xcexcL are plated into flat-bottomed 96 well plates (Corning, N.Y.) and incubated with 50 xcexcL of serially diluted supernatants in the presence of a final concentration of 0.5 xcexcg/mL of actinomycin D (Wako, Japan) at 37xc2x0 C. in 5% CO2 for 18 hours. After incubation, the culture medium is removed and viable cells are stained with 0.2% crystal violet dissolved in 20% ethanol. The cells are washed with tap water and air-dried at room temperature. Resulting crystal violet is dissolved in 100 xcexcl of 100% methanol and the optical density is determined at 595 nm on a BIO-RAD plate reader (Richmond, Calif.). The concentration of TNFxcex1 is determined using human recombinant TNFxcex1 (Wako, Japan) as a standard.
TNFxcex1 enzyme immuno assay: TNFxcex1 levels in culture supernatants are determined by the TiterZyme TNFxcex1 EIA kit (PerSeptive Biosystems, MA), following the instruction manual. Briefly, diluted sample are added onto the 96 well plates precoated with anti-TNFxcex1 monoclonal antibody and incubated at 37xc2x0 C. for 2 hours. After washing wells, anti-TNF polyclonal antibody is added, followed by goat anti-rabbit horseradish peroxidase conjugate. 3,3xe2x80x25,5xe2x80x2-Tetramethylbenzidine (TMB) is used as the substrate. The reaction is stopped by the addition of 1N-HCl, and the optical density is determined at 450 nm on a BIO-RAD plate reader.
Percent inhibition is determined by comparing the absorbance of vehicle treated cells with drug treated cells. Linear regression analysis of the means of the inhibition values are used to determine the IC50.
Some compounds prepared in the Working Examples as described below were tested by this method, and showed an IC50 value of 100 xcexcM to 10 xcexcM with respect to inhibition of TNFxcex1 biosynthesis.
The ability of the compounds of the formula (I) to inhibit CAM expression may be demonstrated in vitro by the following procedures 3 and 4.
Test compounds are diluted with media to obtain final testing concentrations. HUVECs (1.2xc3x97104/well) grown in flat-bottomed, 96 well culture plates (Corning, N.Y.) are stimulated with human TNFxcex1 (3 U/mL, Wako, Tokyo, Japan) in the presence or absence of test compounds. Cells are incubated for 6 hours, then washed in PBS, fixed in 4% paraformaldehyde for 15 minutes, washed and stored for 1-3 days at 4xc2x0 C. in PBS.
Adhesion molecules are detected using ELISA. Cells are incubated with a primary murine antibody to either ICAM-1 (0.5 xcexcg/mL) (BBA#3, RandD Systems) or E-selectin (0.5 xcexcg/mL) (BBA#1, RandD Systems) at room temprature for 2 hours. Anti-mouse Ig, peroxidase-linked species-specific F(abxe2x80x2)2 fragment (from sheep) (Amersham; 1:2500 dilution) is used as the second antibody, followed by the addition of peroxidase substrate, o-phenylenediamine (2.2 mM) and hydrogen peroxide (3.9 mM). The absorbance of each well is read with a Bio-Rad plate reader at 490 nm, and the background at 655 nm is subtracted. The absorbance of nonstimulated HUVECs is subtracted from the absorbance values of TNFxcex1-stimulated cells. Percent inhibition is determined by comparing the absorbance values of vehicle treated cells with that of drug treated cells. Linear regression analysis of the means of the inhibition values are used to determine the IC50.
Some compounds prepared in the Working Examples as described below were tested by this method, and showed an IC50 value of 100 nM to 10 xcexcM with respect to inhibition of the CAM expression.
HL-60 cells are induced to differentiate into granulocyte-like cells by 1.25% DMSO in RPMI-1640 supplemented with 10% heat-inactivated FCS for 5-6 days. The cells are then incubated with 300 xcexcM of a fluorescent dye, 5(6)-carboxyl fluorescein diacetate, for 30 minutes at 37xc2x0 C. and washed three times with Hank""s solution. HUVECs (1.2xc3x97104/well) grown in 96 well plates are simultaneously treated with the test compounds which are diluted with media to obtain final testing concentrations and 30 U/mL TNFxcex1 for 6 hours. Labeled cells (5xc3x97105/well) are added to TNFxcex1- stimulated HUVECs in a final volume of 0.1 xcexcmL, gently washed four times with warm Hank""s solution, and remaining cells are lysed with 1% Nonidet P-40. The number of adherent cells are determined by measuring the fluorescence intensity using a Fluoroscan II (excitation at 485 nm and emission at 538 nm). Percent inhibition is determined by comparing the fluorescence intensity of vehicle treated cells with that of drug treated cells. Linear regression analysis of the means of the inhibition values are used to determine the IC50s.
Some compounds prepared in the Working Examples as described below were tested by this method, and showed an IC50 value of 100 nM to 10 xcexcM with respect to inhibition of the adhesion of HL-60 to HUVECs stimulated by TNFxcex1.
The following representative examples are illustrative of the invention and are not intended as a restriction on the scope of the invention.